Chiral piperidine scaffolds are prevalent as the common cores of a large number of active pharmaceuticals in medical chemistry. This review outlined the diversity of chiral piperidine scaffolds in recently approved drugs, and also covers the scaffolds in leads and drug candidates. The significance of chiral piperidine scaffolds in drug design is also discussed in this article. With the introduction of chiral piperidine scaffolds into small molecules, the exploration of drug-like molecules can be benefitted from the following aspect: (1) modulating the physicochemical properties; (2) enhancing the biological activities and selectivity; (3) improving pharmacokinetic properties; and (4) reducing the cardiac hERG toxicity. Given above, chiral piperidine-based discovery of small molecules will be a promising strategy to enrich our molecules' library to fight against diseases.

Targeting histone deacetylases (HDACs) has become an important focus in cancer inhibition. The pharmacophore of HDAC inhibitors (HDACis) reported so far is composed of three parts: a zinc-binding group (ZBG), a hydrophobic cavity-binding linker, and a surface-recognition cap interacting with HDAC surface located at the rim of active site cavity. This study aims to discover novel HDAC1 inhibitors with potent antitumor activities through modifying the cap and ZBG based on the structures of two marketed oral HDACis: chidamide and entinostat (MS-275). In this work, a series of benzamide derivatives were designed, synthesized, and evaluated for their antitumor activity. The structures of novel compounds were confirmed by 1H NMR (nuclear magnetic resonance) and ESI-MS (electrospray ionization mass spectrometry), and all target compounds were tested in both HDAC1 enzymatic inhibitory activity and cellular antiproliferative activity. Our data showed that the potent compound 3j exhibited good HDAC1 enzyme inhibitory activity and high antitumor cell proliferation activity against a selected set of cancer cells (PC-3, HCT-116, HUT-78, Jurkat E6–1, A549, Colo205, and MCF-7 cells) with no observed effects on human normal cells. In particular, compound 3j inhibited HDAC1 over the other tested HDAC isoforms (HDAC2, HDAC6, and HDAC8). Encouraged by this, the safety characteristics, molecular docking, preliminary pharmacokinetic characteristics, and antitumor effect in vivo of compound 3j were further investigated. Our data showed that compound 3j demonstrated acceptable safety profiles and favorable oral pharmacokinetic properties. Moreover, compound 3j could bind well with HDAC1 and showed significant antitumor activity in a PC-3 tumor xenograft model in vivo, though not as potent as positive control entinostat (MS-275). In summary, 3j might have therapeutic potential for the treatment of human cancers.